The present invention relates to new carboxylic acid derivatives, their preparation and use.
Endothelin is a peptide which is composed of 21 amino acids and is synthesized and released by the vascular endothelium. Endothelin exists in three isoforms, ET-1, ET-2 and ET-3. In the following text, xe2x80x9cendothelinxe2x80x9d or xe2x80x9cETxe2x80x9d signifies one or all isoforms of endothelin. Endothelin is a potent vasoconstrictor and has a potent effect on vessel tone. It is known that this vasoconstriction is caused by binding of endothelin to its receptor (Nature, 332, 411-415, 1988; FEBS Letters, 231, 440-444, 1988 and Biochem. Biophys. Res. Commun., 154, 868-875, 1988).
Increased or abnormal release of endothelin causes persistent vasoconstriction in the peripheral, renal and cerebral blood vessels, which may lead to illnesses. It has been reported in the literature that endothelin is involved in a number of illnesses; these include hypertension, myocardial infarct, heart failure, kidney failure, pulmonary hypertension, Raynaud""s syndrome, cerebral vasospasms, atherosclerosis, stroke, benign prostate hypertrophy and asthma (Japan J. Hypertension 12, 79 (1989), J. Vascular Med. Biology 2, 207 (1990), J. Am. Med. Association 264, 2868 (1990), Nature 344, 11 (1990), N. Engl. J. Med. 322, 205 (1989), N. Engl. J. Med.328, 1732 (1993), Nephron 66, 373 (1994), Strake 25, 904 (1994), Nature 365, 759 (1993), J. Mol. Cell. Cardiol. 27, A234 (1995), Cancer Research 56, 663 (1996)).
Accordingly, substances which specifically inhibit the binding of endothelin to the receptor ought also to antagonize the various abovementioned physiological effects of endothelin and therefore be valuable drugs.
The German Patent Application with the file number P 44 36 851.8 describes the following compounds as endothelin receptor antagonists: 
We have now found that certain carboxylic acid derivatives are good inhibitors of endothelin receptors and that these compounds simultaneously have a relatively low plasma binding.
The invention relates to carboxylic acid derivatives of the formula I 
where R is a formyl group, tetrazole [sic], nitrile [sic], a group COOH or a radical which can be hydrolyzed to COOH, and the other substituents have the following meanings:
R2 halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or C1-C4-alkylthio;
X nitrogen or CR14, where R14 is hydrogen or C1-5-alkyl, or CR14 forms together with CR3 a 5- or 6-membered alkylene or alkenylene ring which can be substituted by one or two C1-4-alkyl groups and in which in each case one methylene group can be replaced by oxygen, sulfur, xe2x80x94NH or xe2x80x94NC1-4-alkyl;
R3 halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, xe2x80x94NHxe2x80x94Oxe2x80x94C1-4-alkyl, C1-C4-alkylthio or CR3 is linked to CR14 as indicated above to form a 5- or 6-membered ring;
R4 and R5 (which may be identical or different):
phenyl or naphthyl, each of which can be substituted by one or more of the following radicals: halogen, nitro, cyano, hydroxyl, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, phenoxy, C1-C4-alkylthio, amino, C1-C4-alkylamino or C1-C4-dialkylamino;
phenyl or naphthyl which are connected together in ortho positions by a direct linkage, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO2, NH or N-alkyl group, or C3-C7-cycloalkyl;
R6 C1-C10-alkyl, C3-C10-alkenyl or C3-C10-alkynyl, the radicals each being substituted one or more times by hydroxyl, mercapto, carboxy, 
xe2x80x83where Ry and Rz are, independently of one another, hydrogen or C1-C5-alkyl; sulfonyl, cyano, guanidino;
Z sulfur or oxygen.
The compounds, and the intermediates for preparing them, eg. IV and VI, may have one or more asymmetrically substituted carbon atoms. Such compounds may exist as pure enantiomers and pure diastereomers or as a mixture thereof. The use of an enantiomerically pure compound as active substance is preferred.
The invention furthermore relates to the use of the abovementioned carboxylic acid derivatives for producing drugs, in particular for producing endothelin-receptor inhibitors.
The compounds according to the invention are prepared starting from the epoxides IV, which are obtained in a conventional way, eg. as described in J. March, Advanced Organic Chemistry, 2nd Ed., 1983, pages 862 and 750 from the ketones II or the olefins III: 
Carboxylic acid derivatives of the general formula VI can be prepared by reacting the epoxides of the general formula IV (eg. with R=ROOR10 [sic] with alcohols or thiols of the general formula V where R6 and Z have the meanings stated in claim 1. 
For this purpose, compounds of the general formula IV are heated with a compound of the formula V in the molar ratio of about 1:1 to 1:7, preferably 1 to 3 mol equivalents, at from 50 to 200xc2x0 C., preferably 80 to 150xc2x0 C.
Other functional groups in R6 are initially protected in a conventional way for the reaction with compounds of the formula IV; for example, alcohols can be protected as acetates, diols as acetals and carboxyl groups as esters. The protective groups can be eliminated after the reaction of compounds of the formula VI with VII.
The reaction may also take place in the presence of a diluent. It is possible to use for this purpose all solvents which are inert toward the reagents used.
Examples of such solvents or diluents are water, aliphatic, alicyclic and aromatic hydrocarbons, which may in each case be chlorinated, such as hexane, cyclohexane, petroleum ether, naphtha, benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, ethyl chloride and trichloroethylene, ethers such as diisopropyl ether, dibutyl ether, methyl tert-butyl ether, propylene oxide, dioxane and tetrahydrofuran, ketones such as acetone, methyl ethyl ketone, methyl isopropyl ketone and methyl isobutyl ketone, nitrites such as acetonitrile and propionitrile, alcohols such as methanol, ethanol, isopropanol, butanol and ethylene glycol, esters such as ethyl acetate and amyl acetate, amides such as dimethylformamide and dimethylacetamide, sulfoxides and sulfones, such as dimethyl sulfoxide and sulfolane, bases such as pyridine, N-methylpyrrolidone, cyclic ureas such as 1,3-dimethyl-2-imidazolidinone and 1,3-dimethyl-3,4,5,6-tetra-hydro-2(1H) pyrimidinone.
The reaction is preferably carried out at a temperature in the range from 0xc2x0 C. to the boiling point of the solvent or mixture of solvents.
The presence of a catalyst may be advantageous. Suitable catalysts in this case are strong organic and inorganic acids, and Lewis acids. Examples thereof are, inter alia, sulfuric acid, hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid, boron trifluoride etherate and titanium(IV) alcoholates.
Compounds of the general formula VI can be obtained in enantiomerically pure form by starting from enantiomerically pure compounds of the formula IV and reacting them with compounds of the formula V in the manner described.
It is furthermore possible to obtain enantiomerically pure compounds of the formula VI by carrying out a classical racemate resolution with racemic or diastereomeric compounds of the formula VI using suitable enantiomerically pure bases such as brucine, strychnine, quinine, quinidine, chinchonidine [sic], chinchonine [sic], yohimbine, morphine, dehydroabietylamine, ephedrine (xe2x88x92), (+), deoxyephedrine (+), (xe2x88x92), threo-2-amino-1-(p-nitrophenyl)-1,3-propanediol (+), (xe2x88x92), threo-2-(N,N-dimethylamino)-1-(p-nitrophenyl)-1,3-propanediol (+), (xe2x88x92), threo-2-amino-1-phenyl-1,3-propanediol (+), (xe2x88x92), xcex1-methylbenzylamine (+), (xe2x88x92), xcex1-(1-naphthyl)ethylamine (+), (xe2x88x92), xcex1-(2-naphthyl)ethylamine (+), (xe2x88x92), aminomethylpinone, N,N-dimethyl-1-phenylethylamine, N-methyl-1-phenylethylamine, 4-nitrophenylethylamine, pseudoephedrine, norephedrine, norpseudoephedrine, amino acid derivatives, peptide derivatives.
The compounds of the general formula I according to the invention can be prepared, for example, by reacting the carboxylic acid derivatives of the general formula VI in which the substituents have the stated meaning with compounds of the general formula VII 
where R15 is halogen or R16xe2x80x94SO2xe2x80x94, where R16 can be C1-C4-alkyl, C1-C4-haloalkyl or phenyl. The reaction preferably takes place in one of the abovementioned inert diluents with the addition of a suitable base, ie. a base which deprotonates the intermediate VI, at a temperature in the range from room temperature to the boiling point of the solvent.
Compounds of the formula VII are known, and some of them can be bought, or they can be prepared in a conventional manner.
It is possible to use as base an alkali metal or alkaline earth metal hydride such as sodium hydride, potassium hydride or calcium hydride, a carbonate such as an alkali metal carbonate, eg. sodium or potassium carbonate, an alkali metal or alkaline earth metal hydroxide such as sodium or potassium hydroxide, an organometallic compound such as butyllithium or an alkali metal amide such as lithium diisopropylamide or lithium amide.
Compounds of the formula I can also be prepared by starting from the corresponding carboxylic acids, ie. compounds of the formula I where R1 is hydroxyl, and initially converting these in a conventional way into an activated form, such as a halide, an anhydride or imidazolide, and then reacting the latter with an appropriate hydroxyl compound HOR10. This reaction can be carried out in conventional solvents and often requires the addition of a base, in which case those mentioned above are suitable. These two steps can also be simplified, for example, by allowing the carboxylic acid to act on the hydroxyl compound in the presence of a dehydrating agent such as a carbodiimide.
Compounds of the formula I can also be prepared by starting from the salts of the appropriate carboxylic acids, ie. from compounds of the formula I where R is a group COR1 and R1 is OM, where M can be an alkali metal cation or the equivalent of an alkaline earth metal cation. These salts can be reacted with many compounds of the formula R1-A where A is a conventional nucleofugic leaving group, for example halogen such as chlorine, bromine, iodine or aryl- or alkylsulfonyl which is unsubstituted or substituted by halogen, alkyl or haloalkyl, such as toluenesulfonyl and methylsulfonyl, or another equivalent leaving group. Compounds of the formula R1-A with a reactive substituent A are known or can easily be obtained with general expert knowledge. This reaction can be carried out in conventional solvents and is advantageously carried out with the addition of a base, in which case those mentioned above are suitable.
The radical R in formula I can be varied widely. R is, for example, a group 
where R1 has the following meanings:
a) hydrogen;
b) a succinylimidoxy [sic] group;
c) a 5-membered heteroaromatic system linked via a nitrogen atom, such as pyrrolyl, pyrazolyl, imidazolyl and triazolyl, which may carry one or two halogen atoms, in particular fluorine and chlorine, and/or one or two of the following radicals:
C1-C4-alkyl such as methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, 1-butyl, 2-butyl;
C1-C4-haloalkyl, in particular C1-C2-haloalkyl such as fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl and pentafluoroethyl;
C1-C4-haloalkoxy, in particular C1-C2-haloalkoxy such as difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-1,1,2-trifluoroethoxy and pentafluoroethoxy, in particular trifluoromethoxy;
C1-C4-alkoxy such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, 1,1-dimethylethoxy, in particular methoxy, ethoxy and 1-methylethoxy;
C1-C4-alkylthio such as methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio, 1,1-dimethylethylthio, in particular methylthio and ethylthio;
d) R1 is furthermore a radical 
xe2x80x83where m is 0 or 1 and R7 and R8, which can be identical or different, have the following meanings:
hydrogen,
C1-C8-alkyl, in particular C1-C4-alkyl as mentioned above;
C3-C6-alkenyl such as 2-propenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl--3-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethy-2-propenyl, 1-ethyl-1-methyl-2-propenyl and 1-ethyl-2-methyl-2-propenyl, in particular 2-propenyl, 2-butenyl, 3-methyl-2-butenyl and 3-methyl-2-pentenyl;
C3-C6-alkynyl such as 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-methyl-2-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 4-methyl-2-pentynyl, 1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl and 1-ethyl-1-methyl-2-propynyl, preferably 2-propynyl, 2-butynyl, 1-methyl-2-propynyl and 1-methyl-2-butynyl, in particular 2-propynyl;
C3-C8-cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and [sic] cycloheptyl, cyclooctyl, it being possible for these alkyl, cycloalkyl, alkenyl and alkynyl groups each to carry one to five halogen atoms, in particular fluorine or chlorine, and/or one or two of the following groups:
C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkylthio, C1-C4-haloalkoxy as mentioned above, C3-C6-alkenyloxy, C3-C6-alkenylthio, C3-C6-alkynyloxy, C3-C6-alkynylthio, where the alkenyl and alkynyl constituents present in these radicals preferably correspond to the abovementioned meanings;
C1-C4-alkylcarbonyl such as, in particular, methylcarbonyl, ethylcarbonyl, propylcarbonyl, 1-methylethylcarbonyl, butylcarbonyl, 1-methylpropylcarbonyl, 2-methylpropylcarbonyl and 1,1-dimethylethylcarbonyl;
C1-C4-alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, 1-methylethoxycarbonyl, butyloxycarbonyl, 1-methylpropyloxycarbonyl, 2-methylpropyloxycarbonyl and 1,1-dimethylethoxycarbonyl;
C3-C6-alkenylcarbonyl, C3-C6-alkynylcarbonyl, C3-C6-alkenyloxy-carbonyl and C3-C6-alkynyloxycarbonyl, where the alkenyl and alkynyl radicals preferably have the definitions detailed above;
phenyl, unsubstituted or substituted one or more times, eg. one to three times by halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or C1-C4-alkyl-thio, such as 2-fluorophenyl, 3-chlorophenyl, 4-bromophenyl, 2-methylphenyl, 3-nitrophenyl, 4-cyanophenyl, 2-trifluoromethylphenyl, 3-methoxyphenyl, 4-trifluoroethoxyphenyl, 2-methylthiophenyl, 2,4-dichlorophenyl, 2-methoxy-3-methylphenyl, 2,4-dimethoxyphenyl, 2-nitro-5-cyanophenyl and 2,6-difluorophenyl;
di-C1-C4-alkylamino such as, in particular, dimethylamino, dipropylamino, N-propyl-N-methylamino, N-propyl-N-ethylamino, diisopropylamino, N-isopropyl-N-methylamino, N-isopropyl-N-ethylamino, N-isopropyl-N-propylamino;
R7 and R8 furthermore phenyl which can be substituted by one or more, eg. one to three, of the following radicals: halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or C1-C4-alkylthio as mentioned above in particular;
or R7 and R8 together form a C4-C7-alkylene chain which is closed to form a ring and is unsubstituted or substituted, eg. substituted by C1-C4-alkyl, and which may contain a hetero atom selected from the group of oxygen, sulfur or nitrogen, such as xe2x80x94(CH2)4xe2x80x94, xe2x80x94(CH2)5xe2x80x94, xe2x80x94(CH2)6xe2x80x94, xe2x80x94(CH2)7xe2x80x94, xe2x80x94(CH2)2xe2x80x94Oxe2x80x94(CH2)2xe2x80x94, xe2x80x94CH2xe2x80x94Sxe2x80x94(CH2)3xe2x80x94, xe2x80x94(CH2)2xe2x80x94Oxe2x80x94(CH2)3xe2x80x94; xe2x80x94NHxe2x80x94(CH2)3xe2x80x94, xe2x80x94CH2xe2x80x94NHxe2x80x94(CH2)xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94(CH2)3xe2x80x94;
e) R1 is furthermore a group 
xe2x80x83in which k assumes the values 0, 1 and 2, p assumes the values 1, 2, 3 and 4, and R9 is
C1-C4-alkyl, C1-C4-haloalkyl, C3-C6-alkenyl, C3-C6-alkynyl or unsubstituted or substituted phenyl, as mentioned above in particular;
f) R1 is furthermore a radical OR10 where R10 is:
hydrogen, the cation of an alkali metal such as lithium, sodium, potassium or the cation of an alkaline earth metal such as calcium, magnesium and barium, or an environmentally compatible organic ammonium ion such as tertiary C1-C4-alkylammonium or the ammonium ion;
C3-C8-cycloalkyl as mentioned above, which may carry one to three C1-C4-alkyl groups;
C1-C8-alkyl such as, in particular, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethylbutyl, 2-ethylbutyl, 1-ethyl-2-methylpropyl, which may carry one to five halogen atoms, in particular fluorine and chlorine, and/or one of the following radicals:
C1-C4-alkoxy, C1-C4-alkylthio, cyano, C1-C4-alkylcarbonyl, C3-C8-cycloakyl [sic], C1-C4-alkoxycarbonyl, phenyl, phenoxy or phenylcarbonyl, it being possible for the aromatic radicals in turn each to carry one to five halogen atoms and/or one to three of the following radicals: nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and/or C1-C4-alkylthio as mentioned above in particular;
a C1-C8-alkyl group as mentioned above, which can carry one to five halogen atoms, in particular fluorine and/or chlorine, and carries one of the following radicals: a 5-membered heteroaromatic system containing one to three nitrogen atoms, or a 5-membered heteroaromatic system containing one nitrogen atom and one oxygen or sulfur atom, which system may carry one to four halogen atoms and/or one or two of the following radicals:
nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, phenyl, C1-C4-haloalkoxy and/or C1-C4-alkylthio. Particular mention may be made of: 1-pyrazolyl, 3-methyl-1-pyrazolyl, 4-methyl-1-pyrazolyl, 3,5-dimethyl-1-pyrazolyl, 3-phenyl-1-pyrazolyl, 4-phenyl-1-pyrazolyl, 4-chloro-1-pyrazolyl, 4-bromo-1-pyrazolyl, 1-imidazolyl, 1-benzimidazolyl, 1,2,4-triazol-1-yl, 3-methyl-1,2,4-triazol-1-yl, 5-methyl-1,2,4-triazol-1-yl, 1-benzotriazolyl, 3-isopropyl-5-isoxazolyl, 3-methyl-5-isoxazolyl, 2-oxazolyl, 2-thiazolyl, 2-imidazolyl, 3-ethyl-5-isoxazolyl, 3-phenyl-5-isoxazolyl, 3-tert-butyl-5-isoxazolyl;
a C2-C6-alkyl group which carries in position 2 one of the following radicals: C1-C4-alkoxyimino, C3-C6-alkynyloxyimino, C3-C6-haloalkenyloxyimino or benzyloxyimino;
a C3-C6-alkenyl or C3-C6-alkynyl group, it being possible for these groups in turn to carry one to five halogen atoms;
R10 is furthermore a phenyl radical which can carry one to five halogen atoms and/or one to three of the following radicals: nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and/or C1-C4-alkylthio as mentioned above in particular;
a 5-membered heteroaromatic system which is linked via a nitrogen atom and contains one to three nitrogen atoms and which can carry one or two halogen atoms and/or one or two of the following radicals: C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, phenyl, C1-C4-haloalkoxy and/or C1-C4-alkylthio. Particular mention may be made of: 1-pyrazolyl, 3-methyl-1-pyrazolyl, 4-methyl-1-pyrazolyl, 3,5-dimethyl-1-pyrazolyl, 3-phenyl-1-pyrazolyl, 4-phenyl-1-pyrazolyl, 4-chloro-1-pyrazolyl, 4-bromo-1-pyrazolyl, 1-imidazolyl, 1-benzimidazolyl, 1,2,4-triazol-1-yl, 3-methyl-1,2,4-triazol-1-yl, 5-methyl-1,2,4-triazol-1-yl, 1-benzotriazolyl, 3,4-dichloro-1-imidazolyl;
R10 is furthermore a group 
xe2x80x83where R11 and R12, which can be identical or different, are:
C1-C8-alkyl, C3-C6-alkenyl, C3-C6-alkynyl, C3-C8-cycloalkyl, it being possible for these radicals to carry a C1-C4-alkoxy, C1-C4-alkylthio and/or an unsubstituted or substituted phenyl radical; phenyl which may be substituted by one or more, for example one to three, of the following radicals: halogen, nitro, cyano, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy or C1-C4-alkylthio,
where these radicals correspond to those mentioned above in particular;
or R11 and R12 together form a C3-C12-alkylene chain which may carry one to three C1-C4-alkyl groups and may contain a hetero atom from the group of oxygen, sulfur and nitrogen;
g) R1 is furthermore a radical 
xe2x80x83where R13 is:
C1-C4-alkyl, C3-C6-alkenyl, C3-C6-alkynyl, C3-C8-cycloalkyl, it being possible for these radicals to carry a C1-C4-alkoxy, C1-C4-alkylthio and/or phenyl radical;
phenyl, unsubstituted or substituted;
h) R1 is a radical 
where R13 has the abovementioned meaning.
R can furthermore be: tetrazole [sic] or nitrile [sic].
With a view to the biological effect, preferred carboxylic acid derivatives of the general formula I, both as pure enantiomers and pure diastereomers or as a mixture thereof, are those in which the substituents have the following meanings:
R2 the C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and C1-C4-alkylthio groups and halogen atoms specified for R1, in particular chlorine, methyl, methoxy, ethoxy, di-fluoromethoxy and trifluoromethoxy;
X nitrogen or CR14 where
R14 hydrogen or alkyl, or CR14 forms together with CR3 a 4- or 5-membered alkylene or alkenylene ring in which, in each case, a methylene group can be replaced by oxygen or sulfur, such as xe2x80x94CH2-CH2xe2x80x94Oxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94Oxe2x80x94, in particular hydrogen, xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94CH(CH3)xe2x80x94CH(CH3)xe2x80x94Oxe2x80x94, xe2x80x94C(CH3)xe2x95x90C(CH3)xe2x80x94Oxe2x80x94, xe2x80x94CHxe2x95x90C(CH3)xe2x80x94Oxe2x80x94 or xe2x80x94C(CH3)xe2x95x90C(CH3)xe2x80x94S;
R3 the C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and C1-C4-alkylthio groups and halogen atoms mentioned for R1, in particular chlorine, methyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy or is linked to R14 as mentioned above to form a 5- or 6-membered ring;
R4 and R5 are phenyl or naphthyl, each of which can be substituted by one or more, eg. one to three, of the following radicals: halogen, nitro, cyano, hydroxyl, mercapto, amino, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C1-C4-alkylthio, C1-C4-alkylamino, di-C1-C4-alkylamino, C1-C4-alkylcarbonyl, C1-C4-alkoxycarbonyl;
phenyl or naphthyl which are connected together in ortho positions by a direct linkage, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO2, NH or N-alkyl group, or C3-C7-cycloalkyl;
R6 C1-C4-alkyl, C3-C5-alkenyl, where the radicals are each substituted once or twice by hydroxyl, mercapto, carboxyl or cyano;
Z sulfur or oxygen.
Particularly preferred compounds of the formula I, both as pure enantiomers and pure diastereomers or as a mixture thereof, are those in which the substituents have the following meanings:
R2 C1-C4-alkyl, C1-C4-alkoxy,
X nitrogen or CR14 where
R14 is hydrogen or alkyl, or CR14 forms together with CR3 a 4- or 5-membered alkylene or alkenylene ring, such as xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94 or xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94, in which, in each case, a methylene group can be replaced by oxygen or sulfur, such as xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94Oxe2x80x94, in particular hydrogen,
xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94CH(CH3)xe2x80x94CH(CH3)xe2x80x94Oxe2x80x94, xe2x80x94C(CH3)xe2x95x90C(CH3)xe2x80x94Oxe2x80x94, xe2x80x94CHxe2x95x90C(CH3)xe2x80x94Oxe2x80x94or xe2x80x94C(CH3)xe2x95x90C(CH3)xe2x80x94S;
R3 the C1-C4-alkyl-, C1-C4-alkoxy, C1-C4-alkylthio groups mentioned for R1, or is linked to R14 as mentioned above to form a 5- or 6-membered ring;
R4 and R5 phenyl (identical or different), which can be substituted by one or more, eg. one to three, of the following radicals: halogen, nitro, hydroxyl, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkylthio or
R4 and R5 are phenyl groups which are connected together in ortho positions by a direct linkage, a methylene, ethylene or ethenylene group, an oxygen or sulfur atom or an SO2, NH or N-alkyl group; or
R4 and R5 are C3-C7-cycloalkyl;
R6 C1-C3-alkyl, C3-C4-alkenyl, where the radicals are each substituted once or twice by hydroxyl or are substituted once by carboxyl;
Z sulfur or oxygen.
The compounds of the present invention provide a novel therapeutic potential for the treatment of hypertension, pulmonary hypertension, myocardial infarct, angina pectoris, acute kidney failure, renal insufficiency, cerebral vasospasms, cerebral ischemia, subarachnoid hemorrhages, migraine, asthma, atherosclerosis, endotoxic shock, endotoxin-induced organ failure, intravascular coagulation, restenosis after angioplasty, benign prostate hyperplasia, or hypertension or kidney failure caused by ischemia or intoxication, and cancers, especially prostate and skin cancer.
The invention further relates to the combination of compounds of the formula I with inhibitors of the renin-angiotensin system (RAS). RAS inhibitors are disclosed in, for example, EP 634 175.
The combinations according to the invention are suitable for treating disorders for which compounds of the formula I also show efficacy on their own, especially for treating hypertomy [sic] and chronic heart failure.
The good effect of the compounds can be shown in the following tests:
Receptor Binding Studies
Cloned human ETA receptor-expressing CHO cells and guinea pig cerebellar membranes with  greater than 60% ETB compared with ETA receptors were used for the binding studies.
Membrane Preparation
The ETA receptor-expressing CHO cells were grown in F12 medium containing 10% fetal calf serum, 1% glutamine, 100 U/ml penicillin and 0.2% streptomycin (Gibco BRL, Gaithersburg, Md., USA). After 48 h, the cells were washed with PBS and incubated with 0.05% trypsin-containing PBS for 5 min. Neutralization was then carried out with F12 medium, and the cells were collected by centrifugation at 300xc3x97g. To lyze the cells, the pellet was briefly washed with lysis buffer (5 mM tris-HCl, pH 7.4 with 10% glycerol) and then incubated at a concentration of 107 cells/ml of lysis buffer at 4xc2x0 C. for 30 min. The membranes were centrifuged at 20,000xc3x97g for 10 min, and the pellet was stored in liquid nitrogen.
Guinea pig cerebella were homogenized in a Potter-Elvejhem homogenizer and obtained by differential centrifugation at 1000xc3x97g for 10 min and repeated centrifugation of the supernatant at 20,000xc3x97g for 10 min.
Binding Assays
For the ETA and ETB receptor binding assay, the membranes were suspended in an incubation bufer (50 mM tris-HCl, pH 7.4 with 5 mM MnCl2, 40 xcexcg/ml bacitracin and 0.2% BSA) at a concentration of 50 xcexcg of protein per assay mixture and incubated with 25 pM [125I [sic]]-ET1 (ETA receptor assay) or 25 pM [125I [sic]]-RZ3 (ETB receptor assay) in the presence and absence of test substance at 25xc2x0 C. The nonspecific binding was determined using 10xe2x88x927M ET1. After 30 min, filtration through GF/B glass fiber filters (Whatman, England) in a Skatron cell collector (Skatron, Lier, Norway) was carried out to separate free and bound radioligand, and the filters were washed with ice-cold tris-HCl buffer, pH 7.4 with 0.2% BSA. The radioactivity collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.
Functional in Vitro Assay System to Look for Endothelin Receptor (subtype A) Antagonists
This assay system is a functional, cell-based assay for endothelin receptors. When certain cells are stimulated with endothelin 1 (ET1) they show an increase in the intracellular calcium concentration. This increase can be measured in intact cells loaded with calcium-sensitive dyes.
1-Fibroblasts which have been isolated from rats and in which an endogenous endothelin receptor of the A subtype had been detected were loaded with the fluorescent dye Fura 2-an as follows: after trypsinization, the cells were resuspended in buffer A (120 mM NaCl, 5 mM KCl, 1.5 mM MgCl2, 1 mM CaCl2, 25 mM HEPES, 10 mM glucose, pH 7.4) to a density of 2xc3x97106/ml and incubated with Fura 2-am (2 xcexcM), Pluronics [sic] F-127 (0.04%) and DMSO (0.2%) at 37xc2x0 C. in the dark for 30 min. The cells were then washed twice with buffer A and resuspended at 2xc3x97106/ml.
The fluorescence signal from 2xc3x97105 cells per ml with Ex/Em 380/510 was recorded continuously at 30xc2x0 C. The test substances and, after an incubation time of 3 min, ET1 were [lacuna] to the cells, the maximum change in the fluorescence was determined. The response of the cells to ET1 without previous addition of a test substance was used as control and was set equal to 100%.
Testing of ET Antagonists in Vivo
Male SD rats weighing 250-300 g were anesthetized with amorbarbital, artificially ventilated, vagotomized and pithed. The carotid artery and jugular vein were cathetized.
In control animals, intravenous administration of 1 xcexcg/kg ET1 leads to a distinct rise in blood pressure which persists for a lengthy period.
The test animals received an i.v. injection of the test compounds (1 ml/kg) 5 min before the administration of ET1. To determine the ET-antagonistic properties, the rise in blood pressure in the test animals was compared with that in the control animals.
Endothelin-1-induced Sudden Death in Mice
The principle of the test is the inhibition of the sudden heart death caused in mice by endothelin, which is probably induced by constriction of the coronary vessels, by pretreatment with endothelin receptor antagonists. Intravenous injection of 10 nmol/kg of endothelin in a volume of 5 ml/kg of body weight results in death of the animals within a few minutes.
The lethal endothelin-1 dose is checked in each case on a small group of animals. If the test substance is administered intravenously, the endothelin-1 injection which was lethal in the reference group usually takes place 5 min thereafter. With other modes of administration, the times before administration are extended, where appropriate up to several hours.
The survival rate is recorded, and effective doses which protect 50% of the animals (ED 50) from endothelin-induced heart death for 24 h or longer are determined.
Functional Test on Vessels for Endothelin Receptor Antagonists
Segments of rabbit aorta are, after an initial tension of 2 g and a relaxation time of 1 h in Krebs-Henseleit solution at 37xc2x0 C. and pH 7.3-7.4, first induced to contract with K+. After washing out, an endothelin dose-effect plot up to the maximum is constructed.
Potential endothelin antagonists are administered to other preparations of the same vessel 15 min before starting the endothelin dose-effect plot. The effects of the endothelin are calculated as percent of the K+induced contraction. Effective endothelin antagonists result in a shift to the right in the endothelin dose-effect plot.
The compounds according to the invention can be administered orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperotoneally) in a conventional way. Administration can also take place with vapours or sprays through the nasopharyngeal space.
The dosage depends on the age, condition and weight of the patient and on the mode of administration. The daily dose of active substance is, as a rule, about 0.5-50 mg/kg of body weight on oral administration and about 0.1-10 mg/kg of body weight on parenteral administration.
The novel compounds can be used in conventional solid or liquid pharmaceutical administration forms, eg. as uncoated or (film) coated tablets, capsules, powders, granules, suppositories, solutions, ointments, creams or sprays. These are produced in a conventional way. The active substances can for this purpose be processed with conventional pharmaceutical aids such as tablet binders, bulking agents, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, release-slowing agents, antioxidants and/or propellant gases (cf. H. Sucker et al.: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1991). The administration forms obtained in this way normally contain from 0.1 to 90% by weight of the active substance.